tbuckley/cabot-search huggingface dataset:
Cryo-EM of Aβ fibrils from mouse models find tg-APPArcSwe fibrils resemble those found in patients with sporadic Alzheimer’s disease
Authors: Mara Zielinski, Fernanda S. Peralta Reyes, Lothar Gremer, Sarah Schemmert, Benedikt Frieg, Luisa U. Schäfer, Antje Willuweit, Lili Donner, Margitta Elvers, Lars N. G. Nilsson, Stina Syvänen, Dag Sehlin, Martin Ingelsson, Dieter Willbold, Gunnar F. Schröder
Journal: Nature Neuroscience (2023)

The use of transgenic mice displaying amyloid-β (Aβ) brain pathology has been essential for the preclinical assessment of new treatment strategies for Alzheimer's disease. However, the properties of Aβ in such mice have not been systematically compared to Aβ in the brains of patients with Alzheimer's disease. Here, we determined the structures of nine ex vivo Aβ fibrils from six different mouse models by cryogenic-electron microscopy. We found novel Aβ fibril structures in the APP/PS1, ARTE10 and tg-SwDI models, whereas the human type II filament fold was found in the ARTE10, tg-APPSwe and APP23 models. The tg-APPArcSwe mice showed an Aβ fibril whose structure resembles the human type I filament found in patients with sporadic Alzheimer's disease. A detailed assessment of the Aβ fibril structure is key to the selection of adequate mouse models for the preclinical development of novel plaque-targeting therapeutics and positron emission tomography imaging tracers in Alzheimer's disease.
Understanding political divisiveness using online participation data from the 2022 French and Brazilian presidential elections
Authors: Carlos Navarrete, Mariana Macedo, Rachael Colley, Jingling Zhang, Nicole Ferrada, Maria Eduarda Mello, Rodrigo Lira, Carmelo Bastos-Filho, Umberto Grandi, Jérôme Lang, César A. Hidalgo
Journal: Nature Human Behaviour (2023)
Postprandial Metabolite Profiles and Risk of Prediabetes in Young People: A Longitudinal Multicohort Study
Authors: Jesse A. Goodrich, Hongxu Wang, Douglas I. Walker, Xiangping Lin, Xin Hu, Tanya L. Alderete, Zhanghua Chen, Damaskini Valvi, Brittney O. Baumert, Sarah Rock, Kiros Berhane, Frank D. Gilliland, Michael I. Goran, Dean P. Jones, David V. Conti, Leda Chatzi
Journal: Diabetes Care (2023)

OBJECTIVE Prediabetes in young people is an emerging epidemic that disproportionately impacts Hispanic populations. We aimed to develop a metabolite-based prediction model for prediabetes in young people with overweight/obesity at risk for type 2 diabetes. RESEARCH DESIGN AND METHODS In independent, prospective cohorts of Hispanic youth (discovery; n = 143 without baseline prediabetes) and predominately Hispanic young adults (validation; n = 56 without baseline prediabetes), we assessed prediabetes via 2-h oral glucose tolerance tests. Baseline metabolite levels were measured in plasma from a 2-h postglucose challenge. In the discovery cohort, least absolute shrinkage and selection operator regression with a stability selection procedure was used to identify robust predictive metabolites for prediabetes. Predictive performance was evaluated in the discovery and validation cohorts using logistic regression. RESULTS Two metabolites (allylphenol sulfate and caprylic acid) were found to predict prediabetes beyond known risk factors, including sex, BMI, age, ethnicity, fasting/2-h glucose, total cholesterol, and triglycerides. In the discovery cohort, the area under the receiver operator characteristic curve (AUC) of the model with metabolites and known risk factors was 0.80 (95% CI 0.72–0.87), which was higher than the risk factor-only model (AUC 0.63 [0.53–0.73]; P = 0.001). When the predictive models developed in the discovery cohort were applied to the replication cohort, the model with metabolites and risk factors predicted prediabetes more accurately (AUC 0.70 [95% CI 40.55–0.86]) than the same model without metabolites (AUC 0.62 [0.46–0.79]). CONCLUSIONS Metabolite profiles may help improve prediabetes prediction compared with traditional risk factors. Findings suggest that medium-chain fatty acids and phytochemicals are early indicators of prediabetes in high-risk youth.
VP4-2023: Sotorasib 960 mg versus 240 mg in pretreated KRAS G12C advanced NSCLC
Authors: M.J. Hochmair, K. Vermaelen, G. Mountzios, E. Carcereny, C. Dooms, S-H. Lee, E.M. Morocz, T. Kato, T-E. Ciuleanu, G. Dy, M.B.M.C.S. Parente, K.J. O'Byrne, Q.S-C. Chu, G. De Castro, N. Girard, W. Snyder, Q. Tran, W. Kormany, B. Houk, A. Curioni-Fontecedro
Journal: Annals of Oncology (2023)
First-in-Human Study with Preclinical Data of BCL-2/BCL-xL Inhibitor Pelcitoclax in Locally Advanced or Metastatic Solid Tumors
Authors: Nehal J. Lakhani, Drew Rasco, Hengbang Wang, Lichuang Men, Eric Liang, Tommy Fu, Mary C. Collins, Ping Min, Yan Yin, Matthew S. Davids, Dajun Yang, Yifan Zhai
Journal: Clinical Cancer Research (2023)

Abstract Purpose: B-cell lymphoma-extra-large (BCL-xL) regulates apoptosis and is an attractive anticancer therapeutic target. However, BCL-xL inhibition also kills mature platelets, hampering clinical development. Using an innovative prodrug strategy, we have developed pelcitoclax (APG-1252), a potent, dual BCL-2 and BCL-xL inhibitor. Aims of this study were to characterize the antitumor activity and safety of pelcitoclax and explore its underlying mechanisms of action (MOA). Patients and Methods: Cell line–derived xenograft and patient-derived xenograft (PDX) models were tested to evaluate antitumor activity and elucidate MOA. Subjects (N = 50) with metastatic small-cell lung cancer and other solid tumors received intravenous pelcitoclax once or twice weekly. Primary outcome measures were safety and tolerability; preliminary efficacy (responses every 2 cycles per RECIST version 1.1) represented a secondary endpoint. Results: Pelcitoclax exhibited strong BAX/BAK‒dependent and caspase-mediated antiproliferative and apoptogenic activity in various cancer cell lines. Consistent with cell-based apoptogenic activity, pelcitoclax disrupted BCL-xL:BIM and BCL-xL:PUMA complexes in lung and gastric cancer PDX models. Levels of BCL-xL complexes correlated with tumor growth inhibition by pelcitoclax. Combined with taxanes, pelcitoclax enhanced antitumor activity by downregulating antiapoptotic protein myeloid cell leukemia-1 (MCL-1). Importantly, pelcitoclax was well tolerated and demonstrated preliminary therapeutic efficacy, with overall response and disease control rates of 6.5% and 30.4%, respectively. Most common treatment-related adverse events included transaminase elevations and reduced platelets that were less frequent with a once-weekly schedule. Conclusions: Our data demonstrate that pelcitoclax has antitumor activity and is well tolerated, supporting its further clinical development for human solid tumors, particularly combined with agents that downregulate MCL-1.
Inhaled recombinant GM-CSF reduces the need for whole lung lavage and improves gas exchange in autoimmune pulmonary alveolar proteinosis patients
Authors: Ilaria Campo, Brenna C. Carey, Elena Paracchini, Zamir Kadija, Annalisa De Silvestri, Giuseppe Rodi, Mara De Amici, Cristina Torre, Michele Zorzetto, Matthias Griese, Federica Meloni, Angelo Guido Corsico, Bruce C. Trapnell, Francesca Mariani
Journal: European Respiratory Journal (2023)

Rationale Whole lung lavage (WLL) is a widely accepted palliative treatment for autoimmune pulmonary alveolar proteinosis (aPAP) but does not correct myeloid cell dysfunction or reverse the pathological accumulation of surfactant. In contrast, inhaled recombinant granulocyte–macrophage colony-stimulating factor (rGM-CSF) is a promising pharmacological approach that restores alveolar macrophage functions including surfactant clearance. Here, we evaluate WLL followed by inhaled rGM-CSF (sargramostim) as therapy of aPAP. Methods 18 patients with moderate-to-severe aPAP were enrolled, received baseline WLL, were randomised into either the rGM-CSF group (receiving inhaled sargramostim) or control group (no scheduled therapy) and followed for 30 months after the baseline WLL. Outcome measures included additional unscheduled “rescue” WLL for disease progression, assessment of arterial blood gases, pulmonary function, computed tomography, health status, biomarkers and adverse events. Patients requiring rescue WLL were considered to have failed their assigned intervention group. Results The primary end-point of time to first rescue WLL was longer in rGM-CSF-treated patients than controls (30 versus 18 months, n=9 per group, p=0.0078). Seven control patients (78%) and only one rGM-CSF-treated patient (11%) required rescue WLL, demonstrating a 7-fold increase in relative risk (p=0.015). Compared to controls, rGM-CSF-treated patients also had greater improvement in peripheral arterial oxygen tension, alveolar–arterial oxygen tension difference, diffusing capacity of the lungs for carbon monoxide and aPAP biomarkers. One patient from each group withdrew for personal reasons. No serious adverse events were reported. Conclusions This long-term, prospective, randomised trial demonstrated inhaled sargramostim following WLL reduced the requirement for WLL, improved lung function and was safe in aPAP patients. WLL plus inhaled sargramostim may be useful as combined therapy for aPAP.
Moving Toward Personalized Colorectal Cancer Follow-Up Care
Authors: Dong Hang, Markus Dines Knudsen, Mingyang Song
Journal: JAMA Oncology (2023)

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Development and prospective validation of postoperative pain prediction from preoperative EHR data using attention-based set embeddings
Authors: Ran Liu, Rodrigo Gutiérrez, Rory V. Mather, Tom A. D. Stone, Laura A. Santa Cruz Mercado, Kishore Bharadwaj, Jasmine Johnson, Proloy Das, Gustavo Balanza, Ekenedilichukwu Uwanaka, Justin Sydloski, Andrew Chen, Mackenzie Hagood, Edward A. Bittner, Patrick L. Purdon
Journal: npj Digital Medicine (2023)

Abstract Preoperative knowledge of expected postoperative pain can help guide perioperative pain management and focus interventions on patients with the greatest risk of acute pain. However, current methods for predicting postoperative pain require patient and clinician input or laborious manual chart review and often do not achieve sufficient performance. We use routinely collected electronic health record data from a multicenter dataset of 234,274 adult non-cardiac surgical patients to develop a machine learning method which predicts maximum pain scores on the day of surgery and four subsequent days and validate this method in a prospective cohort. Our method, POPS, is fully automated and relies only on data available prior to surgery, allowing application in all patients scheduled for or considering surgery. Here we report that POPS achieves state-of-the-art performance and outperforms clinician predictions on all postoperative days when predicting maximum pain on the 0–10 NRS in prospective validation, though with degraded calibration. POPS is interpretable, identifying comorbidities that significantly contribute to postoperative pain based on patient-specific context, which can assist clinicians in mitigating cases of acute pain.
Cytomulate: accurate and efficient simulation of CyTOF data
Authors: Yuqiu Yang, Kaiwen Wang, Zeyu Lu, Tao Wang, Xinlei Wang
Journal: Genome biology (2023)

Recently, many analysis tools have been devised to offer insights into data generated via cytometry by time-of-flight (CyTOF). However, objective evaluations of these methods remain absent as most evaluations are conducted against real data where the ground truth is generally unknown. In this paper, we develop Cytomulate, a reproducible and accurate simulation algorithm of CyTOF data, which could serve as a foundation for future method development and evaluation. We demonstrate that Cytomulate can capture various characteristics of CyTOF data and is superior in learning overall data distributions than single-cell RNA-seq-oriented methods such as scDesign2, Splatter, and generative models like LAMBDA.
Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia
Authors: Yang Liu, Stefan Karlsson
Journal: Leukemia (2023)

Abstact Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure disorder characterized by erythroid hypoplasia. It primarily affects infants and is often caused by heterozygous allelic variations in ribosomal protein (RP) genes. Recent studies also indicated that non-RP genes like GATA1 , TSR2 , are associated with DBA. P53 activation, translational dysfunction, inflammation, imbalanced globin/heme synthesis, and autophagy dysregulation were shown to contribute to disrupted erythropoiesis and impaired red blood cell production. The main therapeutic option for DBA patients is corticosteroids. However, half of these patients become non-responsive to corticosteroid therapy over prolonged treatment and have to be given blood transfusions. Hematopoietic stem cell transplantation is currently the sole curative option, however, the treatment is limited by the availability of suitable donors and the potential for serious immunological complications. Recent advances in gene therapy using lentiviral vectors have shown promise in treating RPS19 -deficient DBA by promoting normal hematopoiesis. With deepening insights into the molecular framework of DBA, emerging therapies like gene therapy hold promise for providing curative solutions and advancing comprehension of the underlying disease mechanisms.
Outsmarting trogocytosis to boost CAR NK/T cell therapy
Authors: Faezeh Ramezani, Ahmad Reza Panahi Meymandi, Behnia Akbari, Omid Reza Tamtaji, Hamed Mirzaei, Christine E. Brown, Hamid Reza Mirzaei
Journal: Molecular Cancer (2023)

Abstract Chimeric antigen receptor (CAR) NK and T cell therapy are promising immunotherapeutic approaches for the treatment of cancer. However, the efficacy of CAR NK/T cell therapy is often hindered by various factors, including the phenomenon of trogocytosis, which involves the bidirectional exchange of membrane fragments between cells. In this review, we explore the role of trogocytosis in CAR NK/T cell therapy and highlight potential strategies for its modulation to improve therapeutic efficacy. We provide an in-depth analysis of trogocytosis as it relates to the fate and function of NK and T cells, focusing on its effects on cell activation, cytotoxicity, and antigen presentation. We discuss how trogocytosis can mediate transient antigen loss on cancer cells, thereby negatively affecting the effector function of CAR NK/T cells. Additionally, we address the phenomenon of fratricide and trogocytosis-associated exhaustion, which can limit the persistence and effectiveness of CAR-expressing cells. Furthermore, we explore how trogocytosis can impact CAR NK/T cell functionality, including the acquisition of target molecules and the modulation of signaling pathways. To overcome the negative effects of trogocytosis on cellular immunotherapy, we propose innovative approaches to modulate trogocytosis and augment CAR NK/T cell therapy. These strategies encompass targeting trogocytosis-related molecules, engineering CAR NK/T cells to resist trogocytosis-induced exhaustion and leveraging trogocytosis to enhance the function of CAR-expressing cells. By overcoming the limitations imposed by trogocytosis, it may be possible to unleash the full potential of CAR NK/T therapy against cancer. The knowledge and strategies presented in this review will guide future research and development, leading to improved therapeutic outcomes in the field of immunotherapy.
<i>Notes from the Field:</i> A Cluster of Multi-Strain Invasive Pneumococcal Disease Among Persons Experiencing Homelessness and Use of Pneumococcal Conjugate Vaccine — El Paso County, Colorado, 2022
Authors: Jessica Callaway, Kristi Durbin, Haley Zachary, Meghan M. Barnes, Miwako Kobayashi, Sopio Chochua, Natalia Gayou, Bernadette Albanese
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Persons experiencing homelessness are often at increased risk for invasive pneumococcal disease (IPD)* due to underlying health conditions or risk factors (risk conditions) (1,2).Homelessness alone is not an indication for pneumococcal vaccination according to current Advisory Committee on Immunization Practices (ACIP) recommendations (3): adults aged ≥65 years or 19-64 years with certain underlying medical conditions or risk factors † with no previous or unknown history of receipt of pneumococcal conjugate vaccine (PCV) should receive 1 dose of either 20-valent or 15-valent PCV (PCV20 or PCV15, respectively).On November 29, 2022, El Paso (Colorado) County Public Health (EPCPH) was informed by a single hospital of three cases of IPD among persons experiencing homelessness, with all illness onset dates occurring within a single week.
Progress Toward Measles Elimination — Worldwide, 2000–2022
Authors: Anna A. Minta, Matt Ferrari, Sebastien Antoni, Allison Portnoy, Alyssa Sbarra, Brian Lambert, Cynthia Hatcher, Christopher H. Hsu, Lee Lee Ho, Claudia Steulet, Marta Gacic-Dobo, Paul A. Rota, Mick N. Mulders, Anindya Sekhar Bose, William Perea Caro, Patrick O’Connor, Natasha S. Crowcroft
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Measles is a highly contagious, vaccine-preventable disease that requires high population immunity for transmission to be interrupted. All six World Health Organization regions have committed to eliminating measles; however, no region has achieved and sustained measles elimination. This report describes measles elimination progress during 2000-2022. During 2000-2019, estimated coverage worldwide with the first dose of measles-containing vaccine (MCV) increased from 72% to 86%, then declined to 81% in 2021 during the COVID-19 pandemic, representing the lowest coverage since 2008. In 2022, first-dose MCV coverage increased to 83%. Only one half (72) of 144 countries reporting measles cases achieved the measles surveillance indicator target of two or more discarded cases per 100,000 population in 2022. During 2021-2022, estimated measles cases increased 18%, from 7,802,000 to 9,232,300, and the number of countries experiencing large or disruptive outbreaks increased from 22 to 37. Estimated measles deaths increased 43% during 2021-2022, from 95,000 to 136,200. Nonetheless, an estimated 57 million measles deaths were averted by vaccination during 2000-2022. In 2022, measles vaccination coverage and global surveillance showed some recovery from the COVID-19 pandemic setbacks; however, coverage declined in low-income countries, and globally, years of suboptimal immunization coverage left millions of children unprotected. Urgent reversal of coverage setbacks experienced during the COVID-19 pandemic can be accomplished by renewing efforts to vaccinate all children with 2 MCV doses and strengthening surveillance, thereby preventing outbreaks and accelerating progress toward measles elimination.
<i>Notes from the Field</i>: Surveillance of Silicosis Using Electronic Case Reporting — California, December 2022–July 2023
Authors: Jennifer Flattery, Chelsea Woolsey, Melanie Epstein-Corbin, David J. Blackley, Robert J. Harrison, Kristin J. Cummings
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Electronic case reporting (eCR) (1) is a promising rapid reporting mechanism, whereby electronic health records (EHRs) automatically generate and transmit a disease report to jurisdictional public health agencies in real time using previously established criteria.All 50 U.S. states and other jurisdictions are connected to the eCR infrastructure.The Reportable Conditions Knowledge Management System (RCKMS),* a component of the eCR infrastructure, is a real-time decision support service that processes reports according to jurisdictional reporting requirements with criteria defined by Council of State and Territorial Epidemiologists' position statements (1).Health care organizations automatically generate and send an initial case report to the eCR infrastructure when trigger criteria, such as diagnosis codes or laboratory results, are met within their EHRs.Therefore, for all participating California health care organizations, if a health care encounter involves COVID-19 or mpox, an initial case report is generated and sent to the eCR infrastructure for processing.When there is a match between the initial case report triggered by an EHR, and a reportable condition rule is entered into RCKMS by a jurisdictional public health agency, the initial case report is routed by the eCR infrastructure to the public health agency.Other conditions can be added to public health agency reporting rules.Silicosis is a progressive, incurable, fibrotic lung disease caused by inhalation of respirable crystalline silica dust produced in industries such as construction, quarrying, and coal mining (2).A resurgence of silicosis among young workers fabricating engineered stone (quartz) countertops in California and in countries including Australia, Israel, and Spain has focused attention on the need for timely case identification for primary and secondary prevention (2-5).In December 2022, the California Department of Public Health (CDPH) added reporting rules for silicosis to RCKMS, so that any initial case report received by the eCR infrastructure from health care provider EHRs that includes a silicosis diagnosis in the patient's problem list is sent to CDPH for silicosis surveillance.The purpose of this study was to evaluate the utility of eCR for identifying cases of silicosis in California.This study was reviewed and approved by the California Committee for the Protection of Human Subjects institutional review board.
Vitamin B12 is a limiting factor for induced cellular plasticity and tissue repair
Authors: Marta Kovatcheva, Elena Melendez, Dafni Chondronasiou, Federico Pietrocola, Raquel Bernad, Adrià Caballe, Alexandra Junza, Jordi Capellades, Adrián Holguín-Horcajo, Neus Prats, Sylvere Durand, Meritxell Rovira, Oscar Yanes, Camille Stephan-Otto Attolini, Guido Kroemer, Manuel Serrano
Journal: Nature Metabolism (2023)

Abstract Transient reprogramming by the expression of OCT4, SOX2, KLF4 and MYC (OSKM) is a therapeutic strategy for tissue regeneration and rejuvenation, but little is known about its metabolic requirements. Here we show that OSKM reprogramming in mice causes a global depletion of vitamin B 12 and molecular hallmarks of methionine starvation. Supplementation with vitamin B 12 increases the efficiency of reprogramming both in mice and in cultured cells, the latter indicating a cell-intrinsic effect. We show that the epigenetic mark H3K36me3, which prevents illegitimate initiation of transcription outside promoters (cryptic transcription), is sensitive to vitamin B 12 levels, providing evidence for a link between B 12 levels, H3K36 methylation, transcriptional fidelity and efficient reprogramming. Vitamin B 12 supplementation also accelerates tissue repair in a model of ulcerative colitis. We conclude that vitamin B 12 , through its key role in one-carbon metabolism and epigenetic dynamics, improves the efficiency of in vivo reprogramming and tissue repair.